The genetic basis of tumorigenic responses to endogenous or inoculated C-type viruses is being studied in a variety of strain crosses. The major determinants of spontaneous leukemias in hybrids with AKR have been shown to be the endogenous ecotropic virus inducing loci, the Fv-1 gene, and the Rmcf gene. The progeny of crosses of AKR with certain strains of mice (C57L, C57Br, C57BL/6.Fv-1(n), SJL) which are Fv-1(n) and, based on in vitro assays, Rmcf(s), show restriction of MCF generation and low frequency of thymic lymphoma. The basis for this type of restriction is under study. The Rmcf gene, which specifically inhibits infectivity of MCF viruses, is a strong determinant of leukemogenicity by MCF 247 and Friend helper virus. The effect of this gene on a variety of retroviral diseases is under study, including spontaneous B-cell lymphomas in high virus congenic mice, inoculated with erythroblastic or myeloid leukemia-inducing viruses, and mice inoculated with a neuroparalytic retrovirus. No clear effect of the restrictive Rmcf allele on Moloney, Gross, or SL3-3 virus-induced T cell lymphomagenesis has been observed.